Solid preparations for oral use

ABSTRACT

Solid preparations for oral use for facilitating the administration in a small dose of KRP-297, which is a ligand common to peroxisome proliferator-activated receptors PPAR α and PPAR γ (i.e., nuclear receptors) and has an effect of ameliorating insulin resistance, which contain the drug ingredient in a uniform content and can be easily and quantitatively taken. By preparing solid preparations for oral use composed of a trace amount of the drug ingredient together with pharmaceutical carriers, it is possible to provide tablets which contain the drug component in a uniform content and can be easily and quantitatively taken.

TECHNICAL FIELD

The present invention relates to solid preparations for oral use whichcontains a small amount of(±)-5-[(2,4-dioxothiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]-benzamide(hereinafter abbreviated as KRP-297), and makes it possible to formulatepowder of KRP-297 into an oral tablet capable of taking easily. KRP-297is a common ligand against peroxisome proliferator-activated receptor γ(PPAR γ) concerning in the differentiation induction of adipocytes andPPAR a concerning in lipid-metabolism, among the isoforms of PPAR thatis nuclear receptor, and has an improving action on the insulinresistance.

BACKGROUND TECHNOLOGIES

KRP-297 is a thiazolidine-2,4-dione derivative with novel structure(Japanese Unexamined Patent Publication No. Hei 9-48711) and has apotent blood glucose-lowering action and lipid-lowering action (NomuraM. et al, Bioorg. Med. Chem. Lett., 9 (1999), 533–538), which is nowunder clinical. No solid preparations for oral use that is uniform inthe content of a small amount of active ingredient and capable of takingquantitatively and easily on clinical application of KRP-297 has beenknown.

The subject of the invention is to provide solid preparations for oraluse that contains a small amount of active ingredient uniformly and iscapable of taking quantitatively on clinical application of KRP-297.

DISCLOSURE OF THE INVENTION

The inventors have prepared solid preparations for oral use thatcontains a small amount of active ingredient uniformly and is capable oftaking quantitatively on clinical application of KRP-297, leading to thecompletion of the invention. The inventive solid preparations for oraluse is an oral solid preparations (tablet) with uniform content,prepared by formulating a small amount of KRP-297 with drug-makingcarriers (excipient, disintegrator, binder, lubricant and coating agent)and by granulating, pressing into tablet and coating.

The process for preparing the inventive pharmaceutical comprises thesteps of mixing fine powdery KRP-297 with the excipient (for example,saccharides such as lactose and glucose, sugar alcohols such asD-sorbitol and mannitol, celluloses such as crystalline cellulose,starches such as corn starch, etc., preferably lactose and crystallinecellulose) and the disintegrator (for example, celluloses such ascalcium carboxymethylcellulose, low substituted hydroxypropylcellulose,sodium cross carmelose and methylcellulose, cross povidone, partiallypregelatinized starch, etc., preferably low substitutedhydroxypropylcellulose), and further by adding the binder (for example,celluloses such as hydroxypropylcellulose, hydroxypropylmethylcellulose,ethylcellulose and methylcellulose, gelatin, polyvinyl alcohol,polyvinyl pyrrolidone, etc., preferably polyvinyl alcohol), followed bygranulation. For the granulation, the fluidized bed granulator can beused well.

Following this, the lubricant (for example, magnesium stearate, calciumstearate, talc, hydrogenated oil, etc., preferably magnesium stearate)is added, the mixture is pressed into tablet, and further the coatingagent (for example, celluloses such as hydroxypropylcellulose,hydroxypropylmethylcellulose, ethyl-cellulose and methylcellulose,hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer,carnauba wax, etc., preferably hydroxypropylmethylcellulose and carnaubawax) is coated, thereby the oral solid preparations or tablet capable oftaking more easily can be obtained.

In the tablet obtained in this way, 0.25 mg to 5 mg of KRP-297 can becontained uniformly as an active ingredient per tablet, and, by takingorally, the pharmaceutical can be taken quantitatively.

BEST EMBODIMENT TO PUT THE INVENTION INTO PRACTICE

In following, the invention will be illustrated based on the examples,but the invention is not confined to these examples.

EXAMPLE 1

Per tablet, 0.25 mg of KRP-297, 78.55 mg of lactose, 26.2 mg ofcrystalline cellulose and 12 mg of low substitutedhydroxypropylcellulose were mixed. Then, using a fluidized bedgranulator, an aqueous solution of 2.4 mg-equivalent polyvinyl alcoholwas added thereto, and the mixture was granulated and dried. Afterscreening and rectifying the granules, 0.6 mg of magnesium stearate wereadded and mixed, followed by pressing into tablet to obtain uncoatedtablets. Onto the uncoated tablets thus obtained, 5 mg-equivalenthydroxypropylmethylcellulose 2910 were coated, and 0.001 mg of carnaubawax was added and mixed to obtain film-coated tablets.

EXAMPLE 2

Per tablet, 1 mg of KRP-297, 91.1 mg of lactose, 30.4 mg of crystallinecellulose and 14 mg of low substituted hydroxypropylcellulose weremixed. Then, using a fluidized bed granulator, an aqueous solution of2.8 mg-equivalent polyvinyl alcohol was added thereto, and the mixturewas granulated and dried. After screening and rectifying the granules,0.7 mg of magnesium stearate were added and mixed, followed by pressinginto tablet to obtain uncoated tablets. Onto the uncoated tablets thusobtained, 5 mg-equivalent hydroxypropylmethylcellulose 2910 were coated,and 0.001 mg of carnauba wax was added and mixed to obtain film-coatedtablets.

EXAMPLE 3

Per tablet, 2.5 mg of KRP-297, 92 mg of lactose, 28 mg of crystallinecellulose and 14 mg of low substituted were mixed. Then, using afluidized bed granulator, an aqueous solution of 2.8 mg-equivalentpolyvinyl alcohol was added thereto, and the mixture was granulated anddried. After screening and rectifying the granules, 0.7 mg of magnesiumstearate were added and mixed, followed by pressing into tablet toobtain uncoated tablets. Onto the uncoated tablets thus obtained, 5mg-equivalent hydroxypropylmethylcellulose 2910 were coated, and 0.002mg of carnauba wax were added and mixed to obtain film-coated tablets.

EXAMPLE 4

Per tablet, 5 mg of KRP-297, 103 mg of lactose, 32 mg of crystallinecellulose and 16 mg of low substituted hydroxypropylcellulose weremixed. Then, using a fluidized bed granulator, an aqueous solution of3.2 mg-equivalent polyvinyl alcohol was added thereto, and the mixturewas granulated and dried. After screening and rectifying the granules,0.8 mg of magnesium stearate were added and mixed, followed by pressinginto tablet to obtain uncoated tablets. Onto the uncoated tablets thusobtained, 5 mg-equivalent hydroxypropylmethylcellulose 2910 were coated,and then 0.002 mg of carnauba wax were added and mixed to obtainfilm-coated tablets.

EXAMPLE 5

Per tablet, 0.25 mg of KRP-297, 80.75 mg of lactose, 24 mg ofcrystalline cellulose and 12 mg of low substitutedhydroxypropylcellulose were mixed. Then, using a fluidized bedgranulator, an aqueous solution of 2.4 mg-equivalent polyvinyl alcoholwas added thereto, and the mixture was granulated and dried. Afterscreening and rectifying the granules, 0.6 mg of magnesium stearate wereadded and mixed, followed by pressing into tablet to obtain uncoatedtablets. Onto the uncoated tablets thus obtained, 4 mg-equivalenthydroxypropylmethylcellulose 2910 were coated, and then 0.002 mg ofcarnauba wax were added and mixed to obtain film-coated tablets.

EXAMPLE 6

Per tablet, 1 mg of KRP-297, 93.5 mg of lactose, 28 mg of crystallinecellulose and 14 mg of low substituted hydroxypropylcellulose weremixed. Then, using a fluidized bed granulator, an aqueous solution of2.8 mg-equivalent polyvinyl alcohol was added thereto, and the mixturewas granulated and dried. After screening and rectifying the granules,0.7 mg of magnesium stearate were added and mixed, followed by pressinginto tablet to obtain uncoated tablets. Onto the uncoated tablets thusobtained, 5 mg-equivalent hydroxypropylmethylcellulose 2910 were coated,and 0.002 mg of carnauba wax were added and mixed to obtain film-coatedtablets.

EXPERIMENTAL EXAMPLE

With the tablets obtained in respective examples, test was performedaccording to the uniformity test of content in the 13th revisionJapanese Pharmacopoeia. As a result, uniform pharmaceuticals which meetthe standard were obtained in all cases.

Results are shown in Table 1.

TABLE 1 Test results of uniformity of content of KRP-297 tablet Example1 Example 2 Example 3 Example 4 Example 5 Example 6 Av. value (%) 98.4100.9 99.9 99.8 100.4 100.1 Range (%) 96.8~102.9 100.2~101.5 98.7~100.998.6~101.1 99.4~100.7 99.1~101.1 Judgment value (%)  5.3  2.0  1.6  1.8 1.3  1.6 Judgment value: Value less than 15% conforts to the standard.

UTILIZABILITY IN THE INDUSTRY

According to the invention, an solid preparations for oral use ofKRP-297, being a common ligand against PPAR α and PPAR γ and having animproving action on the insulin resistance, have been provided.

On clinical application of KRP-297, it was difficult to takequantitatively, if keeping it powdery as it is, because of a smallamount of it. However, by mixing with drug-making carriers and bymolding, the oral solid preparation that is uniform in the content ofactive ingredient and easy in the handling has been completed and it hasbecome possible to take quantitatively and simply.

1. A solid preparation comprising 0.25 to 5 mg of(±)-5-[(2,4-dioxo-thiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamideas an active ingredient and at least one carrier, wherein said solidpreparation is suitable for oral administration and wherein(±)-5-[(2,4-dioxo-thiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamideis uniformly contained in said solid preparation thereby making(±)-5-[(2,4-dioxo-thiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamideeasy to orally administer, wherein the solid preparation is prepared bymixing 0.25 to 5 mg of(±)-5-[(2,4-dioxo-thiazolidine-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]-methyl]benzamide,lactose, crystalline cellulose, and low substitutedhydroxypropylcellulose to obtain a mixture; granulating with drying inthe presence of an aqueous solution of polyvinyl alcohol with afluidized bed granulator to obtain a granulated product; then mixing thegranulated product with magnesium stearate after screening andrectifying the granules from the granulator to obtain a second mixture;and pressing the second mixture into a tablet.
 2. The solid preparationof claim 1, wherein after the tablet is formed, the tablet is coated toform a coated tablet.